In this project we seek to advance the understanding of the physiology and pathophysiology of the hypothalamic-pituitary- adrenal axis. The role of stress-related hormones in normal and disease states is being examined, and clinical applications for these hormones are seeked. The recent discovery of the structure of corticotropin releasing hormone (CRH) and the development of sensitive assays for measuring stress-related hormones and their receptors have led to rapid progress in this field. Major progress has been made in three areas: 1) Clinical application of CRH: An ovine CRH (oCRH) stimulation test has been developed that is useful in the differential diagnosis of adrenal insufficiency, Cushing's syndrome, and pseudo-Cushing's syndrome (psychiatric hypercortisolism. The human CRH (hCRH) analog is useful in studying the physiology of the pituitary-adrenal axis. The oCRH stimulation test and measurement of CSF CRH have increased our understanding of the pathophysiology of Cushing's syndrome, depression and anorexia nervosa. 2) Regulation of the hypothalamic-pituitary-adrenal axis in vivo and in vitro: The regulation of the axis by opioids, vasopressin, oxytocin, and glucocorticoids has been studied in vivo. Neurotransmitter and feedback regulation of hypothalamic CRH secretion has been examined in vitro in a newly established hypothalamic organ culture system. Athletes have a hyperfunctional pituitary-adrenal axis in the resting state. Hypothalamic-pituitary-adrenal axis reactivity and personality traits have been correlated in developing adolescents. 3) Role and actions of glucocorticoids: The effects of glucocorticoids upon the cardiovascular system during surgical stress are merely permissive. Glucocorticoid resistance is associated with normal size glucocorticoid receptor protein that has decreased affinity for glucocorticoid and normal size mRNA.